TRPM7 maintains progenitor-like features of neuroblastoma cells: implications for metastasis formation

Oncotarget. 2015 Apr 20;6(11):8760-76. doi: 10.18632/oncotarget.3315.

Abstract

Neuroblastoma is an embryonal tumor derived from poorly differentiated neural crest cells. Current research is aimed at identifying the molecular mechanisms that maintain the progenitor state of neuroblastoma cells and to develop novel therapeutic strategies that induce neuroblastoma cell differentiation. Mechanisms controlling neural crest development are typically dysregulated during neuroblastoma progression, and provide an appealing starting point for drug target discovery. Transcriptional programs involved in neural crest development act as a context dependent gene regulatory network. In addition to BMP, Wnt and Notch signaling, activation of developmental gene expression programs depends on the physical characteristics of the tissue microenvironment. TRPM7, a mechanically regulated TRP channel with kinase activity, was previously found essential for embryogenesis and the maintenance of undifferentiated neural crest progenitors. Hence, we hypothesized that TRPM7 may preserve progenitor-like, metastatic features of neuroblastoma cells. Using multiple neuroblastoma cell models, we demonstrate that TRPM7 expression closely associates with the migratory and metastatic properties of neuroblastoma cells in vitro and in vivo. Moreover, microarray-based expression profiling on control and TRPM7 shRNA transduced neuroblastoma cells indicates that TRPM7 controls a developmental transcriptional program involving the transcription factor SNAI2. Overall, our data indicate that TRPM7 contributes to neuroblastoma progression by maintaining progenitor-like features.

Keywords: differentiation; metastasis; neuroblastoma; snai2; trpm7.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Neoplasms / secondary
  • Cell Division
  • Cell Line, Tumor
  • Cell Movement
  • Disease Progression
  • Gene Expression Regulation, Developmental
  • Gene Expression Regulation, Neoplastic
  • Heterografts
  • Humans
  • Liver Neoplasms / secondary
  • Mice
  • Neoplasm Metastasis / genetics*
  • Neoplasm Proteins / physiology*
  • Neoplastic Stem Cells / cytology*
  • Neural Crest / cytology
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology*
  • Protein-Serine-Threonine Kinases / physiology*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Signal Transduction / genetics
  • Snail Family Transcription Factors
  • TRPM Cation Channels / physiology*
  • Transcription Factors / physiology
  • Transcription, Genetic
  • Tumor Microenvironment

Substances

  • Neoplasm Proteins
  • RNA, Small Interfering
  • SNAI2 protein, human
  • Snai2 protein, mouse
  • Snail Family Transcription Factors
  • TRPM Cation Channels
  • Transcription Factors
  • Protein-Serine-Threonine Kinases
  • TRPM7 protein, human